1. Introduction
Although primary and secondary preventive measures (especially statin
and antiplatelet therapies) have reduced the risk of death due to
cardiovascular diseases to a certain extent, cardiovascular diseases
caused by atherosclerosis remain the main chronic diseases globally,
with high mortality and disability rates, medical risks, and medical
costs [1]. Thus, developing effective therapies remains a challenge
in the management of millions of patients with atherosclerosis.
Growing evidence indicates that inflammation is a key regulator of
atherosclerosis development and fragile plaque formation [2]. Cell
death, especially necroptosis, is closely associated with inflammation.
Lin et al. reported a large number of necroptotic cells and upregulated
expression of receptor interacting protein kinase-3 (RIP3) in the
necrotic core of progressive plaques [3]. Moreover, in human carotid
plaques, the expression of necroptosis-related proteins such as RIP3
pseudokinase mixed lineage kinase domain-like (MLKL), and phosphorylated
MLKL is upregulated [4]. Thus, cell necroptosis may be a promising
target for the treatment of atherosclerosis [5]. In addition, using
both non-lineage and vascular smooth muscle cell (VSMC) lineage-tracing
models, recent studies have shown that similar to human coronary
atheromas, VSMCs contribute to the majority of cells in
ApoE−/− mouse atherosclerosis plaques [6,7] and
undergo various forms of cell death, typically lead to the formation of
a lipid-rich necrotic core within the evolving intimal lesion.
Therefore, regulating the death of VSMC-derived foam cells will provide
clinical benefits. Multiple pathogenic factors associated with
cardiovascular diseases can cause cell necroptosis. Oxidized low-density
lipoprotein (ox-LDL), a major proatherogenic factor, exerts a
proinflammatory effect [8] and is rich in plaque necrotic core.
However, whether ox-LDL induces the necroptosis of VSMC-derived foam
cell and enlargement of the necrotic core is unknown.
Ox-LDL causes reactive oxygen species (ROS) to accumulate abnormally in
cells, and ROS are key targets in necroptosis regulation [9].
Therefore, we hypothesized that ROS may play an important role in
ox-LDL-induced cell necroptosis. In our previous study, we found that
C1q/TNF-related protein 9 (CTRP9) inhibits cholesterol-induced
inflammatory cytokine secretion and monocyte adhesion in VSMCs by
activating the AMPK pathway [10]. Activated AMPK can inhibit
oxidative stress-induced mitochondrial dysfunction [11] and is
essential to understand whether CTRP9 plays a protective role against
ox-LDL-induced necroptosis in VSMC-derived foam cells and
atherosclerosis. In this study, we aimed to evaluate the effect of
ox-LDL on VSMC-derived foam cell necroptosis, determine the role of
VSMC-derived foam cell necroptosis in inflammation, and examine whether
and how CTRP9 protects against ox-LDL-induced cell dysfunction.
Furthermore, we determined the effect of CTRP9 on atherosclerosis. Our
study could help in understanding the initiation and development of
atherosclerosis and a serve as a potential therapeutic target for
atherosclerosis.